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Title page for ETD etd-05232017-122303

Type of Document

Dissertation

Author

Zike, Isaac Daniel

Author's Email Address

isaac.d.zike@vanderbilt.edu

URN

etd-05232017-122303

Title

Investigating the Role of Obsessive-Compulsive Disorder Candidate Gene
SLC1A1 in Basal Ganglia and Repetitive Behavior

Degree

PhD

Department

Pharmacology

Advisory Committee

Advisor Name

Title

Ariel Deutch

Committee Chair

Carrie Jones

Committee Member

Gregg Stanwood

Committee Member

James Bodfish

Committee Member

Jeremy Veenstra-VanderWeele

Committee Member

Keywords

obsessive

compulsive

glutamate

neuroscience

Date of Defense

2017-05-31

Availability

unrestricted

Abstract

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter EAAT3/EAAC1. Despite this, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a new model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in 1) locomotor activity, 2) stereotypy, and 3) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This is accompanied by reduced D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations both at baseline and following amphetamine challenge in the dorsal striatum. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on pre-synaptic dopaminergic function. Collectively, these findings represent the first indication that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.